Significance: Although the overwhelming majority of COVID-19-related deaths are due to respiratory failure, little is known about the host response to SARS-CoV-2 in lung parenchyma. By profiling the lung and colon transcriptome and lung proteome of nine patients who died of COVID-19 during the first wave of the pandemic in Wuhan, China, we obtained molecular insights into the host response to severe SARS-CoV-2 infection. Interestingly, all samples had a low viral burden, a finding that suggests the patients’ deaths may be due to uncontrolled host inflammatory processes rather than an active viral infection. Taken together, our findings shed light on COVID-19 pathophysiology and offer potential therapeutic targets for severe COVID-19 disease.

Significance Statement: Coronavirus disease 2019 (COVID-19) is a new contagious disease. Previous studies reported AKI with varying results regarding the incidence, severity, and outcomes. This study provides detailed clinical data of 81 patients critically ill with COVID-19 and a prolonged disease course, and provides renal pathologic findings from ten deceased patients with AKI in a single intensive care unit in Wuhan, China. The incidence of AKI was 50.6%, with 41.5% of cases of AKIs were Kidney Disease Improving Global Outcomes (KDIGO) stage 3. The primary pathological findings were those of acute tubular injury. Nucleic acid tests and immunohistochemistry failed to detect the virus in kidney tissues. Older age and serum IL-6 levels were risk factors of AKI. KDIGO stage 3 AKI independently predicted death. Background: The incidence, severity, and outcomes of AKI in COVID-19 varied in different reports. In patients critically ill with COVID-19, the clinicopathologic characteristics of AKI have not been described in detail. Methods: This is a retrospective cohort study of 81 patients critically ill with COVID-19 in an intensive care unit. The incidence, etiologies, and outcomes of AKI were analyzed. Pathologic studies were performed in kidney tissues from ten deceased patients with AKI. Results: A total of 41 (50.6%) patients experienced AKI in this study. The median time from illness to AKI was 21.0 (IQR, 9.5–26.0) days. The proportion of Kidney Disease Improving Global Outcomes (KDIGO) stage 1, stage 2, and stage 3 AKI were 26.8%, 31.7%, and 41.5%, respectively. The leading causes of AKI included septic shock (25 of 41, 61.0%), volume insufficiency (eight of 41, 19.5%), and adverse drug effects (five of 41, 12.2%). The risk factors for AKI included age (per 10 years) (HR, 1.83; 95% CI, 1.24 to 2.69; P=0.002) and serum IL-6 level (HR, 1.83; 95% CI, 1.23 to 2.73; P=0.003). KDIGO stage 3 AKI predicted death. Other potential risk factors for death included male sex, elevated D-dimer, serum IL-6 level, and higher Sequential Organ Failure Assessment score. The predominant pathologic finding was acute tubular injury. Nucleic acid tests and immunohistochemistry failed to detect the virus in kidney tissues. Conclusions: AKI was a common and multifactorial complication in patients critically ill with COVID-19 at the late stage of the disease course. The predominant pathologic finding was acute tubular injury. Older age and higher serum IL-6 level were risk factors of AKI, and KDIGO stage 3 AKI independently predicted death.

Increased tau acetylation at K274 and K281 has been observed in the brains of Alzheimer's disease (AD) patients and animal models, and mitochondrial dysfunction are noticeable and early features of AD. However, the effect of acetylated tau on mitochondria has been unclear until now. Here, we constructed three type of tau forms, acetylated tau mutant by mutating its K274/K281 into Glutamine (TauKQ) to mimic disease-associated lysine acetylation, the non-acetylation tau mutant by mutating its K274/K281 into Arginine (TauKR) and the wild-type human full-length tau (TauWT). By overexpression of these tau forms in vivo and in vitro, we found that, TauKQ induced more severe cognitive deficits with neuronal loss, dendritic plasticity damage and mitochondrial dysfunctions than TauWT. Unlike TauWT induced mitochondria fusion, TauKQ not only induced mitochondria fission by decreasing mitofusion proteins, but also inhibited mitochondrial biogenesis via reduction of PGC-1a/Nrf1/Tfam levels. TauKR had no significant difference in the cognitive and mitochondrial abnormalities compared with TauWT. Treatment with BGP-15 rescued impaired learning and memory by attenuation of mitochondrial dysfunction, neuronal loss and dendritic complexity damage, which caused by TauKQ. Our data suggested that, acetylation at K274/281 was an important post translational modification site for tau neurotoxicity, and BGP-15 is a potential therapeutic drug for AD.

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents—findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1β). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

MiR-497-5p inhibits cell proliferation and invasion by targeting KCa3.1 in angiosarcoma miR-497-5p inhibits cell proliferation and invasion by targeting KCa3.1 in angiosarcoma